This Proposal for the continuation of the Clinical Research Center for Acute Spinal Cord Injuries at New York University will examine several interrelated hypotheses concerning the pathogenesis and treatment of spinal cord injury (SCI) at both the laboratory and clinical level. The major hypothesis to be tested is that the irreversible lesion resulting from injury to the spinal cord is neither immediate nor complete, and that appropriate therapy can be designed and instituted to ameliorate the multiple pathogenic mechanisms initiated by the trauma. Individual Projects will look at innovative treatment regimens in experimental and clinical SCI. These have been developed as information concerning the pathogenesis of SCI has been provided by the component Projects of this Proposal. We present three principal theories concerning the mechanisms by which trauma to the spinal cord may lead to irreversible damage. The major emphasis of this Proposal will be to test each of these hypotheses by themselves and for correlations that may suggest a common pathogenesis underlying more than one of them. The first concerns the role of endogenous opiate peptides in the damage to the spinal cord and the ability of the opiate antagonist, naloxone, to improve neurological recovery after SCI. The second deals with the causes of ischemia to the spinal cord, the effects of ischemia on the spinal cord and methods available to prevent a decrease in spinal cord blood flow. The third hypothesis is that SCI initiates a series of pathologic free radical reactions which produce damage to critical biomembranes in the spinal cord. These pathologic reactions are amenable to control by specific pharmacologic methods. The concept of the development of an irreversible spinal cord lesion at some time after trauma carries with it the inherent view that the initial events are not sufficient by themselves to cause devitalization of tissue but require the progressive development of interrelated pathologic responses. It is to these latter events that therapy will be directed.